When rats are exposed to the acetylcholinesterase inhibitor, methanesulfonyl fluoride (MSF), in utero during the last 2 weeks of gestation, the resulting pups show a changed REM sleep architecture and substantial learning and memory deficits as adults. All preliminary work indicates that these animals have a heightened cholinergic tone and that this may be a reasonable animal model of Rett's Syndrome. The work proposed in this application has 3 major aims; 1) To test whether MSF in utero exposure effects on sleep and learning and memory are the result of an increased cholinergic tone, 2) To test whether MSF in utero exposure leads to alterations in either presynaptic or postsynaptic cholinergic mechanisms, or both, and 3) To test whether the effects of MSF in utero exposure are the result of its anti-acetylcholinesterase actions or to its serine protease inhibitor effects, or both. To achieve the first aim, changes in sleep architecture and learning and memory will be tested with a battery of cholinomimetic and anticholinergic drugs. In general, if the notion that these animals have a heightened cholinergic tone is correct, it is anticipated that cholinomimetic drugs will increase REM sleep while having little or negative effects on learning and memory and that anticholinergic substances should have a smaller attenuation of REM sleep in these animals while improving learning and memory. To achieve the second aim, the content, compartmentalization, and release of acetylcholine will be investigated along with changes to choline uptake, choline acetyltransferase activity, and both muscarinic and nicotinic receptor densities and affinities. The results from this work should identify changes to either presynaptic and/or postsynaptic mechanisms. In order to achieve the third aim, animals will be exposed in utero to a pure acetylcholinesterase inhibitor, a general serine protease inhibitor, both types of inhibitors, or MSF. The resulting pups will then be recorded for changes in sleep architecture and tested in a radial arm maze for learning and memory.